natural history in fabry patients with ivs4+919g>a mutation

Conditions: Fabry Disease, Cardiac Variant

Summary: fabry disease is caused by the deficiency or absence of alpha-galactosidase a (α-gal a) activity, leading to progressive deposition of glycosphingolipids, mainly globotriaosylceramide (gb3), in the lysosomes of multiple tissues and organs. in taiwan, dr. niu first revealed a surprisingly high incidence (approximately one in 1,600 males) of a cardiac variant gla splicing mutation, ivs4+919g\>a, in newborn screening. patients who carried the ivs4 + 919g \> a mutation and were older than 40 years had a higher prevalence of hypertrophic cardiomyopathy. endocardial biopsy of these patients with hypertrophic cardiomyopathy showed significant gb3 accumulation in the cardiomyocytes. although the hotspot ivs4+919g\>a mutation is now being observed with greater frequency, understanding of the natural course of cardiac variant fabry disease with this specific mutation remains limited. therefore, our study would like to conduct a study to approach the natural history among patients with chinese hotspot late-onset fabry mutation ivs4+919g\>a through family pedigree analysis.

fabry disease is caused by the deficiency or absence of alpha-galactosidase a (α-gal a) activity, leading to progressive deposition of glycosphingolipids, mainly globotriaosylceramide (gb3), in the lysosomes of multiple tissues and organs. the frequency of classic fabry disease has been estimated as one in 40,000, and its symptoms typically manifest during childhood, including acroparesthesias, angiokeratoma, corneal opacities, and anhidrosis (desnick et al. 2001; ries et al. 2005). originally thought to be less severe in females (desnick et al. 2001), more recent evidence indicates that symptoms of this x-linked disorder can manifest as severely in females as in males (mehta et al. 2004; wilcox et al. 2008), although they generally occur later in life and show greater variation in severity among female patients (deegan et al. 2006). atypical, late-onset phenotypes have been reported that lack these classic symptoms but instead present with cardiac (nakao et al. 1995), renal (nakao et al. 2003), or cerebrovascular disease (brouns et al. 2010). the frequency of atypical fabry disease is unknown, but it has been suggested to be more common than previously believed (nakao et al. 1995). in taiwan, dr. niu first revealed a surprisingly high incidence (approximately one in 1,600 males) of a cardiac variant gla splicing mutation, ivs4+919g\>a, in newborn screening (chong et al. 2008). affected males with ivs4+919g\>a mutation typically lack the angiokeratomas, acroparesthesias, hypohidrosis, gastrointestinal abnormalities and corneal opacities that are characteristic of the classic, early-onset, more severe phenotype and may manifest cardiac disease with lvh leading to hcm in the third to sixth decades of life (desnick et al. 2001, von scheidt w, et al. 1991, nakao et al. 1995, nakao et al. 2003). in dr. niu's study, patients who carried the ivs4 + 919g \> a mutation and were older than 40 years had a higher prevalence of hypertrophic cardiomyopathy (72% of males and 35% of females) (tai et al., 2012). endocardial biopsy of these patients with hypertrophic cardiomyopathy showed significant gb3 accumulation in the cardiomyocytes which is the typical pathological change in patient with classical fabry disease. lin et al's previous study (lin et al. 2010) showed that a high proportion of adults (\>40 years of age) carrying the ivs4 +919g\>a mutation experienced microalbuminuria and retinal vessel tortuosity, but symptoms involving these organs were very mild and did not cause significant morbidity. although the hotspot ivs4+919g\>a mutation is now being observed with greater frequency, understanding of the natural course of cardiac variant fabry disease with this specific mutation remains limited. primary objective : * to map the ivs4 family tree and identify obligate carriers with chinese hotspot late-onset fabry mutation ivs4+919g\>a through pedigree analysis. * to explore and enhance the understanding of the clinical manifestation, disease severity and natural history of patient with chinese hotspot late-onset fabry mutation ivs4+919g\>a in taiwan. primary end point : - completeness of ivs4 family tree mapping and obligate carrier identification within their family pedigree. definition of family tree completeness: - enroll first generation (newborn), at least one member from second (parent) and third generation (grandparent) for a complete ivs4 family tree mapping. secondary endpoint : - collect and analyze medical history, genetic and biochemical assessment data. perform egfr and albumin to creatinine ratio (acr) measurement for renal function assessment, perform echocardiography and electrocardiography for cardiac function assessment.

Eligibility criteria:
inclusion criteria: * fabry ivs4 female newborn family members. * patients and/or their legal representatives who are willing to provide written informed consent exclusion criteria: * no blood relatives to the ivs4 female newborn family